Targeting 20s proteasome with computational tools

Proteasome emerged as a rational therapeutic approach in cancer and several other diseases, since ubiquitin proteasome pathway plays a pivotal role in intracellular protein degradation and turnover in eukaryotic cells. FDA (2003) approved bortezomib as the first proteasome inhibitor, other proteasome inhibitors were approved and others are in clinical trials. However, their use is still restricted to certain types of blood cancers and show severe side effects, dose limiting toxicity and innate or acquired resistance. Our goal is to understand proteasome inhibitors resistance to discover and develop new proteasome inhibitors for cancer treatment. We studied the structural and dynamic behavior of the proteasome B5 catalytic unit and effect of mutations inside/close to the binding pocket. A conformational/structural evaluation of the native and mutated proteasome was performed based on molecular dynamics simulations using 5LE5 X-ray structure. All the calculations were performed with GROMACS 2016 software. Results will be presented and discussed.